Protein phosphatase 2A (PP2A), a family of the major serine/threonine phosphatases in cells, is widely considered a tumor suppressor (Van Hoof, C. et al. 2004; Westermarck, J. et al. 2008). Inhibition of PP2A is thought to be a precursor of malignant transformation of human cells and some PP2A inhibitors such as okadaic acid are associated with tumorigenesis and tumor progression (Junttila, M. R. et al. 2007; Suganuma, M. et al. 1988), Structurally, PP2A has three subunits and each subunit has alternative isoforms (Mumby, M. 2007), resulting in over 60 heterotrimeric holoenzymes (Gwinn, D. et al. 2013). Because of the complicated constitutive and various signaling pathways involving PP2A, this ubiquitous phosphatase may play distinct roles in different tissue and disease states. For instance, the B55a regulatory subunit of PP2A was shown to enhance the survival of human fibrosarcoma cells during glutamine deprivation (Reid, M. A. et al. 2013), while inhibition of the B56γ subunit induces tumorigenic transformation of human embryonic kidney cells (Chen, W. et al. 2004), thereby acting like B56α as a tumor suppressor (Arnold, H. K. et al. 2008). This diversity of PP2A function in tumorigenesis suggests in certain circumstances targeting PP2A may be an effective cancer strategy.
Cantharidin, a natural product isolated from Mylabris sidae, and several cantharidin derivatives have PP2A inhibitory activity, and have been used as anti-cancer agents for decades (Hart, M. E. et al. 2004; Li, W. et al. 2010; Liu, D. et al. 2009; McCluskey, A. et al. 2000). The mechanism by which PP2A exerts anti-cancer activity is believed be abrogation of cell cycle checkpoints and induction of mitotic catastrophe (Kaley, P. et al. 2011). Although cantharadin has previously been used in the treatment of hepatomas and has shown efficacy against multidrug-resistant leukemia cell lines (Efferth, T. et al. 2002), its severe toxicity limits its clinical usefulness. LB100 is a small molecule derivative of cantharadin with significantly less toxicity. Previous pre-clinical studies have shown that LB100 can enhance the cytotoxic effects of temozolomide, doxorubicin, and radiation therapy against glioblastoma (GBM), metastatic pheochromocytoma, and pancreatic cancer (Wei, D. et al. 2013; Lu, J. et al. 2009; Zhang, C. et al. 2010b; Martiniova, L. et al. 2011). LB100 is also undergoing a phase 1 study in combination with docetaxel for the treatment of solid tumors (Chung, V. 2013).